Human Telomerase (hTERT) is Directly Regulated by the Non-Telomeric Telomere-Binding Factor TRF2

Human telomerase reverse transcriptase hTERT remains suppressed in most normal adult somatic cells. Resulting erosion of telomeres leads eventually to replicative senescence. Reactivation of hTERT maintains telomeres and triggers progression of >90% human cancers. However any direct causal link between telomeres and telomerase regulation remains unclear. Here we show that the telomere-repeat-binding-factor TRF2 binds to the hTERT promoter and recruits the polycomb-repressor EZH2/PRC2 complex. This is causal for H3K27 trimethylation at the hTERT promoter and represses hTERT in cancer as well as normal cells. TRF2 interacts with hTERT promoter G-quadruplexes. Two highly recurrent hTERT promoter mutations found in many cancers, including ~83% glioblastoma-multiforme, that are known to destabilize hTERT promoter G-quadruplexes, obliterated TRF2 binding in patient-derived primary glioblastoma-multiforme cells. Ligand-induced G-quadruplex stabilization restored TRF2 binding, H3K27-trimethylation and hTERT re-suppression. These results uncover a previously unknown mechanism of hTERT regulation through a telomeric factor, implicating telomere-telomerase molecular links that might be important in neoplastic transformation, ageing and regenerative therapy.